As many as 10% of Americans suffer chronic sleep disturbances, but the genetic mechanisms that control sleep and wake states remain largely unknown. The long-range goal of the proposed studies is to identify secreted proteins that modulate sleep, wakefulness and arousal. Zebrafish will be used as a model system because it displays clear, measurable sleep and wake behaviors and is the only vertebrate system in which such a screen is feasible. The screen will involve the generation of several hundred stably transgenic zebrafish lines that express secreted proteins under an inducible promoter. The library will be made available through the zebrafish stock center and screened for modulators of larval sleep and wakefulness. In addition, the response to mechanical, chemical, thermal and visual cues will be tested. Candidate lines will be further analyzed in secondary screens for developmental and behavioral defects. The isolated peptides will form the foundation to dissect the molecular and neural circuits of sleep. The screen will also provide candidate pathways that might be affected in human sleep disorders and that could be modulated by drugs to treat sleep disorders. PUBLIC HEALTH RELEVANCE: This project aims to identify genes that modulate sleep and wakefulness. The regulation of sleep is poorly understood, and sleep disorders are a major health problem.